Although there are advances in understanding the pathogenesis of multiple myeloma, its causes remain elusive. Risk is increased by 1.5-3-fold in family members of cases, suggesting a genetic contribution. It is possible that plasma cell growth factors and proteins important in B cell differentiation may contribute to risk by increasing the pool of plasma cells available for transformation to myeloma. In prior SPORE supported pilot studies, we found evidence linking polymorphisms (i.e., SNPs) in genes that control two important plasma cell growth factors, interleukin (IL)-6 and insulin-like growth factor (IGF)-1, with susceptibility to multiple myeloma. In addition, we found positive associations between polymorphisms of certain DNA repair genes and multiple myeloma risk. These studies had strong prior hypotheses but small sample sizes, and thus the possibility of false positive results is a. concern. Furthermore, since multiple myeloma disproportionately affects African-Americans and Hispanics (to a lesser degree), it is important to conduct studies in a multi-ethnic setting, whereas the pilot studies included relatively few ethnic minorities. Therefore we propose to confirm these preliminary findings in a larger multi-ethnic sample of 559 cases and 885 controls from 5 separate studies with existing DNA samples, including the Health Professionals Follow-up Study, Nurse's Health Study, and the USC-Hawaii Multi-ethnic Cohort Study, and two population-based case-control studies. We will include several genes in plasma cell growth and B cell differentiation pathways. In choosing the SNPs to examine in this study, we will take into account the ethnic diversity of the participating study populations, as well as considerations related to the structure of the genes of interest. We have developed a powerful software program to choose polymorphisms based on those considerations from HapMap, and we will genotype 1,536 SNPs in 25 genes using well-validated, efficient genotyping technology through the DSC Genotyping Core Facility. We will examine the association of variation in individual genes with myeloma risk, accounting for correlations between SNPs. We will also interact with other SPORE projects to interrogate the function of any SNPs that we observe to be associated with risk. We believe this project enhances the overall value of the SPORE by contributing to the understanding of genetic susceptibility to multiple myeloma, needed for the development of both treatment and prevention strategies.